Use of indole-derived compounds for the preparation of a medicament that can be used to treat diseases related to the splicing process

Active Publication Date: 2007-03-08
UNIV DE MONTPELLIER +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016] The inventors sought to find a new strategy, in particular one that uses molecules capable of inhibiting p

Problems solved by technology

At present, it is estimated that approximately 50% of the point mutations responsible for genetic diseases result in splicing errors.
One of the disadvantages of the strategies developed and cited above to correct or eliminate splicing errors is their cost of production.
Indeed, the cost of producing antisense oligonucleotides that must be modified to improve their stability, and also the cost of producing PNA molecules, is high.
Another disadvantage of the strategies developed and cited above is that they require the use of expression vectors, as for example for the strategy based on the use of trans-splicing.

Method used

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  • Use of indole-derived compounds for the preparation of a medicament that can be used to treat diseases related to the splicing process
  • Use of indole-derived compounds for the preparation of a medicament that can be used to treat diseases related to the splicing process
  • Use of indole-derived compounds for the preparation of a medicament that can be used to treat diseases related to the splicing process

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0300] In vitro inhibition of, splicing of two types of model pre-mRNAs

[0301] The compounds presented in Tables 1 and 2 below were tested in a concentration range of 1 μM, 10 μM and 100 μM, and were selected initially on the basis of their capacity to inhibit, in vitro, the splicing of two types of model pre-mRNAs.

TABLE 1MoleculecodeChemical formulaNomenclatureC1N′-(9-methoxy-5,6,11- trimetyl-6H-pyrido[4,3- b]carbazol-1-yl)-N,N-dimethyl- propane-1,3-diamineC2N′-(9-methoxy-6,11-dimethyl- 6H-pyrido[4,3-b]carbazol-1- yl)-N,N-dimethyl-propane-1,3- diamineC310-chloro-2,6-dimethyl-2H- pyrido[3′,4′:4,5]pyrrolo[2,3- g]isoquinolineC49-hydroxy-5-methyl-6H- pyrido[4,3-b]carbazol-1-yl acetic acid esterC51-(3-dimethylamino- propylamino)5-methyl-6H- pyrido[4,3-b]carbazol-9-olC69-methoxy-5-methyl-6H- pyrido[4,3-b]carbazol-1- carbaldehyde oximeC7N′(9-methoxy-5-methyl-6H- pyrido[4,3-b]carbazol-11-yl)- N,N-dimethyl-propane-1,3- diamineC8N,N-diethyl-N′-(9-methoxy-5- methyl-6H-pyrido[4,3- b]carbazol...

example 2

[0314] In vivo inhibition of the ESE-dependent splicing of GFP (green fluorescent protein) mRNA

[0315] In order to test the efficiency of indole derivatives ex vivo, fibroblast HeLa cell lines were established stably expressing a transgene corresponding to GFP whose sequence was interrupted by an ESE sequence flanked by two identical introns of the human beta-globulin gene described in Example 1 (see FIG. 5A).

[0316] To detect the messenger RNAs arising from, the splicing of this gene, the RT-PCR technique was used with primers in the GFP sequence on each side of the ESE and the PCR products were analyzed on agarose gel.

[0317] In almost all the lines established, a single fragment of 250 base pairs (bp) was amplified by PCR (FIG. 5A, lanes 2 and 3) and it corresponds to an RNA messenger which included the ESE between the two GFP sequences.

[0318] The result indicates that the ESE has a dominant effect and that the RNA messenger produced after splicing contains the two parts of the ...

example 3

[0322] In vivo inhibition of the ESE-dependent splicing of pyruvate dehydrogenase E1α subunit mRNA

[0323] In order to demonstrate the selectivity of the action on ESE sequences by the compounds according to the invention, it was decided to use another model substrate containing two introns whose splicing depends on two different ESE sequences. In this substrate the sequences corresponding to exon 7-intron 7-exon 8 of the gene coding for the pyruvate dehydrogenase E1α subunit (PDH E1α) are inserted downstream from the M3S1 sequence (M3S1-PDH, see FIG. 4A). Intron 7 of this transcript contains a point mutation which creates a high affinity SR hSC35 protein binding site. This mutation, which causes the loss of PDH E1α expression in patients suffering from Leigh syndrome (an encephalopathy in children), leads to the appearance of a cryptic site 46 nucleotides downstream from the authentic 5′ splicing site (FIG. 4A). This substrate, likely to give rise to two products, one with and one w...

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Abstract

The invention relates to indole-derived compounds and to the use of said compounds for the preparation of a medicament that can be used to treat diseases related to the process of splicing pre-messenger RNAs in the cell, such as Frasier syndrome, frontotemporal dementia linked to chromonsoem 17 (a form of Parkinson's disease), Leigh syndrome (a type of encephalopathy), atypical cystic fibrosis, certain neuropathologies including Alzheimer's disease linked to a mutation in the Tau protein, muscle atorphy which affects the SMN (survival of Motor Neuron) gene, depression linked to a serotonin splicing impairment, and certain cancers in which the global splicing process is affected (e.g. breast cancer, colon cancer and certain lymphomas), as well as viral diseases such as AIDS.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present application is a national phase entry under 35 U.S.C. § 371 of International Application No. PCT / FR2004 / 002261 filed Sep. 6, 2004, published in France, which claims priority from French Patent Application No. 0310460 filed Sep. 4, 2003 and French Patent Application No. 0400973 filed Feb. 2, 2004, all of which are incorporated herein by reference.BACKGROUND OF THE INVENTION [0002] The invention relates to novel indole-derived compounds and their use in the preparation of a medicine of use in the treatment of diseases related to the splicing process. [0003] Certain indole-derived compounds, such as ellipticine and aza-ellipticine derivatives, are already known as intercalating molecules which correct errors in genetic expression during the replication process. They have been more specifically described for the treatment of diseases such as cancer, leukemia and AIDS (FR 2 627 493, FR 2 645 861, FR 2 436 786). [0004] The intrace...

Claims

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Application Information

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IPC IPC(8): A61K31/5377A61K31/496A61K31/4745A61K31/403A61K31/437A61K31/4375A61K31/475C07D209/80C07D471/04C07D471/14C07D519/00
CPCA61K31/403A61K31/437A61K31/4375A61K31/4745C07D471/14A61K31/5377C07D209/80C07D471/04A61K31/496A61P1/00A61P11/00A61P15/00A61P19/04A61P25/00A61P25/14A61P25/16A61P25/28A61P31/12A61P31/18A61P35/00A61P43/00
Inventor TAZI, JAMALSORET, JOHANNJEANTEUR, PHILIPPEGRIERSON, DAVID
Owner UNIV DE MONTPELLIER
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